Retinoblastoma protein (RB1) (pRb)

The Retinoblastoma protein (pRb), encoded by the RB1 gene, is a foundational tumor suppressor that governs the G1 to S phase transition of the cell cycle (UniProt P06400). It functions as a transcriptional co-repressor by binding to E2F transcription factors, thereby inhibiting the expression of genes necessary for DNA replication (PubMed PMID: 28273103). Rb pathway–deficient tumor cells arise when this regulatory mechanism is lost through RB1 mutation, deletion, or hyperphosphorylation by Cyclin-dependent kinases (CDK4/6), leading to unchecked cellular proliferation and genomic instability (NIH/NCI). While CDK4/6 inhibitors are highly effective in tumors where the Rb pathway is intact but overactive, they are ineffective in Rb-deficient cells because the primary substrate for the kinase is absent. Consequently, clinical research for Rb-deficient tumors focuses on synthetic lethal approaches, targeting proteins such as Aurora Kinase A or PLK1 to exploit the specific vulnerabilities created by the loss of Rb-mediated cell cycle control (PubMed PMID: 30401617). This target profile is particularly relevant for aggressive malignancies like small cell lung cancer and triple-negative breast cancer where RB1 loss is a frequent driver event.

Other names

RB1p110-RB1Retinoblastoma-associated proteinp105-RbPP110

CDK4/6 inhibitors prevent the phosphorylation of Rb, maintaining it in an active, growth-suppressive state to block the G1-S transition. In Rb-deficient cells, therapeutic strategies utilize synthetic lethality by targeting alternative mitotic regulators like Aurora Kinase A or PLK1 that these cells depend on for survival.